Submissions for variant NM_000548.5(TSC2):c.1832G>A (p.Arg611Gln)

dbSNP: rs28934872

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414340	SCV000491001	pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing	Functional studies indicate that R611Q disrupts the TSC1-TSC2 complex (Nellist et al., 2001; Nellist et al., 2005; Hoogeveen-Westerveld et al., 2011); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31447099, 27542907, 22867869, 15483652, 15798777, 11741832, 27216612, 26703369, 27406250, 29632054, 29129521, 29308833, 29476190, 16032769, 30293248, 31083211, 32555378, 31799751, 32340510, 32313033, 18466115, 30787465, 9463313, 32211034, 21309039)
Invitae	RCV000013205	SCV000544351	pathogenic	Tuberous sclerosis 2	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 611 of the TSC2 protein (p.Arg611Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 10205261, 15595939, 17304050). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12397). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 11741832, 15483652, 18854862, 21309039, 26703369). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491426	SCV000579587	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	The p.R611Q pathogenic mutation (also known as c.1832G>A), located in coding exon 16 of the TSC2 gene, results from a G to A substitution at nucleotide position 1832. The arginine at codon 611 is replaced by glutamine, an amino acid with some highly similar properties. This pathogenic mutation has been shown to inactivate the tuberin-hamartin complex, disrupt the ability of the tuberin protein to chaperone the hamartin protein throughout the cell, disrupt the phosphorylation of the tuberin protein and several downstream target proteins, and to cause the loss of GTPase activity stimulation (Nellist M et al. Hum. Mol. Genet. 2001 Dec; 10(25):2889-98; Nellist M et al. Eur. J. Hum. Genet. 2005 Jan; 13(1):59-68). This pathogenic mutation has been reported as a de novo finding in unrelated individuals with tuberous sclerosis complex (TSC) (Au KS et al. Am. J. Hum. Genet. 1998 Feb; 62(2):286-94), and has also been reported in multiple individuals diagnosed with TSC and infantile spasms (van Eeghen AM et al. Epilepsy Res. 2013 Jan; 103(1):83-7). Another alteration at this codon, p.R611W (c.1831C>T), has also been classified as a pathogenic mutation in the literature (Nellist M et al. Hum. Mol. Genet. 2001 Dec; 10(25):2889-98; Nellist M et al. Eur. J. Hum. Genet. 2005 Jan; 13(1):59-68). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Athena Diagnostics Inc	RCV000414340	SCV000615886	pathogenic	not provided	2019-06-14	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity confirmed plus 1 unconfirmed case.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000013205	SCV000782399	pathogenic	Tuberous sclerosis 2	2016-11-01	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000013205	SCV000840073	pathogenic	Tuberous sclerosis 2	2017-12-04	criteria provided, single submitter	clinical testing	This c.1832G>A (p.Arg611Gln) variant in the TSC2 gene has been reported in multiple unrelated individuals with Tuberous Sclerosis (PMID: 9463313, 10570911, 15595939). Functional studies have shown that the p.Arg611Gln mutant tuberin protein (encoded by the TSC2 gene) has decreased interaction with its binding partner, hamartin, and is unable to inhibit the mTOR pathway properly (PMID: 11741832, 15483652, 15963462, 18302728, 18308511, 21309039). The c.1832G>A variant in TSC2 is not present in the general population. This c.1832G>A (p.Arg611Gln) variant in the TSC2 gene is classified as pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768118	SCV000899051	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-03-30	criteria provided, single submitter	clinical testing	TSC2 NM_000548.4 exon 17 p.Arg611Gln (c.1832G>A): This variant has been reported in the literature in several individuals with tuberous sclerosis, at least one of whom was determined to be de novo (Au 1998 PMID:9463313, van Eeghen 2013 PMID:22867869, Overwater 2016 PMID:27406250). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:12397). Evolutionary conservation and computational predictive tools predict that this variant may impact the protein. Additionally, in vitro functional studies further support an impact to the protein (Nellist 2001 PMID:11741832, Nellist 2005 PMID:15483652). Furthermore, another variant at this same codon (p.Arg611Trp) has been reported in the literature in association with disease and has been seen by our lab in an individual with tuberous sclerosis, further supporting that this region has significance. In summary, this variant is classified as pathogenic based on the data above.
CeGaT Center for Human Genetics Tuebingen	RCV000414340	SCV001334512	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000013205	SCV001423565	pathogenic	Tuberous sclerosis 2	2020-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013205	SCV002040940	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000768118	SCV002778170	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2022-03-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000414340	SCV003799245	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing	The TSC2 c.1832G>A; p.Arg611Gln variant (rs28934872) is described in the literature in several individuals with a clinical diagnosis of tuberous sclerosis complex, including the variant occurring de novo in at least three individuals (Babol-Pokora 2021, Reyna-Fabian 2020, Suspitsin 2018). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 12397) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 611 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.893). Functional studies indicate the variant disrupts the interaction with hamartin and inhibits phosphorylation (Hoogeveen-Westerveld 2011, Nellist 2005). Based on available information, this variant is classified as pathogenic. References: Babol-Pokora K et al. A multistep approach to the genotype-phenotype analysis of Polish patients with tuberous sclerosis complex. Eur J Med Genet. 2021 Oct;64(10):104309. PMID: 34403804. Hoogeveen-Westerveld M et al. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Hum Mutat. 2011 Apr;32(4):424-35. PMID: 21309039. Nellist M et al. Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. Eur J Hum Genet. 2005 Jan;13(1):59-68. PMID: 15483652. Reyna-Fabian ME et al. First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants. Sci Rep. 2020 Apr 20;10(1):6589. PMID: 32313033. Suspitsin EN et al. Pattern of TSC1 and TSC2 germline mutations in Russian patients with tuberous sclerosis. J Hum Genet. 2018 May;63(5):597-604. PMID: 29476190.
Illumina Laboratory Services, Illumina	RCV000414340	SCV003802810	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing	The TSC2 c.1832G>A (p.Arg611Gln) missense variant results in the substitution of arginine at amino acid position 611 with glutamine. Across a selection of available literature, the c.1832G>A variant has been reported in at least 17 individuals with tuberous sclerosis complex, with several described as occurring de novo (PMID: 9463313; PMID: 15595939; PMID: 22867869; PMID: 32555378). Another variant at the same amino acid position, c.1831C>T (p.Arg611Trp), has been reported in a heterozygous state in at least six individuals with tuberous sclerosis complex (PMID: 15595939; PMID: 22867869). The c.1832G>A variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional analysis using mass spectrometry and coimmunoprecipitation determined the c.1832G>A variant is associated with loss of phosphorylation and is inactivated due to protein mis-folding (PMID: 15963462). This variant was identified in a de novo state. Based on the available evidence, the c.1832G>A (p.Arg611Gln) variant is classified as pathogenic for tuberous sclerosis complex.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000013205	SCV004805369	likely pathogenic	Tuberous sclerosis 2	2024-03-25	criteria provided, single submitter	research
OMIM	RCV000013205	SCV000033452	pathogenic	Tuberous sclerosis 2	2000-05-23	no assertion criteria provided	literature only
OMIM	RCV000055317	SCV000033453	pathogenic	Lymphangiomyomatosis	2000-05-23	no assertion criteria provided	literature only
Tuberous sclerosis database (TSC2)	RCV000042946	SCV000066743	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Tuberous sclerosis database (TSC2)	RCV000055317	SCV000083537	not provided	Lymphangiomyomatosis		no assertion provided	curation
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV000013205	SCV000090404	not provided	Tuberous sclerosis 2		no assertion provided	not provided